The overall objectives of this research project are to study the metabolism, excretion and persistence of long-acting narcotics, using methadone, as a prototype, in tolerant humans maintained on methadone and in naive and tolerant animals and to study drug interactions between methadone and agents which may alter its metabolism. Specific recent objectives have included the introduction of a new research application for the use of stable isotopes by developing methods for their use in studies of narcotic metabolism both in vitro and in vivo. Long-term studies on the disposition, excretion and persistence of methadone in rats are in progress. Clinical interactions between methadone and the anti-tuberculosis drug, rifampin, have been observed and studies performed which document significant pharmacological interactions between these two agents. Further studies of these and other drug interactions with methadone are in progress. BIBLIOGRAPHIC REFERENCES: Kreek, M.J.; "Methadone maintenance treatment for chronic opiate addiction." in Medical Aspects of Drug Abuse, ed. R. Richter, Harper and Row, N.Y. (1975), pp. 167-185. Stimmel, B. and M.J. Kreek; "Pharmacologic actions of heroin." in Heroin Dependency; Medical, Economic and Social Aspects, ed. B. Stimmel. Intercontinent Medical Book Corp., N.Y. (1975), pp. 71-87.